One of the significant drawbacks of antitumor or antineoplastic agents is their failure to discriminate between normal dividing cells and tumor cells. When acting on normal dividing cells, these agents cause undesireable side effects, including nausea, apolecia, and bone marrow toxicity. Their cardiotoxicty is a primary contributor to dosage limitation.
Kopecek et al., U.S. Pat. No. 5,037,883, describe a drug conjugate which includes inert synthetic N-(2 hydroxypropyl) methacrylamide polymeric carriers combined through peptide spacers with a bioactive molecule, with a targeting moiety, and with an optional cross-linkage. The peptide spacers contain between 2 and 6 naturally occurring amino acids.
Yang et al., Proc. Natl. Acad. Sci. USA vol. 85, pp. 1189-1193 (1988) describe doxorubicin conjugated with a monoclonal antibody directed to a human melanoma-associated proteoglycan. The conjugate suppresses the growth of established tumor xenografts in nude mice.
Dillman et al., Cancer Research vol. 48, pp. 6097-6102 (1988) describe the superiority of an acid-labile daunorubicin-monoclonal antibody immunoconjugate compared to free acid.
Shen et al., Biochemical and Biophysical Research Communications vol. 102, no. 3, pp. 1048-1054 (1981) describe cis-aconityl spacer between daunomycin and macromolecular carriers.